Protein kinases (PK) are a large set of structurally related phosphoryl transferases having highly conserved structures and catalytic functions. Protein kinases are enzymatic components of the signal transduction pathways which catalyze the transfer of the terminal phosphate from ATP to the hydroxy group of tyrosine, serine and/or threonine residues of proteins, and are therefore categorized into families by the substrates they phosphorylate: Protein Tyrosine Kinases (PTK), and Protein Serine/Threonine Kinases.
Protein kinases play a critical role in the control of cell growth and differentiation and are responsible for the control of a wide variety of cellular signal transduction processes, wherein protein kinases are key mediators of cellular signals leading to the production of growth factors and cytokines. The overexpression or inappropriate expression of normal or mutant protein kinases plays a significant role in the development of many diseases and disorders including, central nervous system disorders such as Alzheimer's, inflammatory disorders such as arthritis, bone diseases such as osteoporosis, metabolic disorders such as diabetes, blood vessel proliferative disorders such as angiogenesis, autoimmune diseases such as rheumatoid arthritis, ocular diseases, cardiovascular disease, atherosclerosis, cancer, thrombosis, psoriasis, restenosis, schizophrenia, pain sensation, transplant rejection and infectious diseases such as viral, and fungal infections.
The agents of the invention act as inhibitors of PDGFR kinase, c-Kit kinase and related receptor and non-receptor tyrosine kinases. PDGFR is activated by binding of the growth factor PDGF to the extracellular portion of the receptor. Upon activation PDGFR phosphorylates many substrate proteins and controls a wide variety of cellular functions including proliferation and migration. PDGFR mediates these effects on multiple cell types including those of the mesenchymal lineage, fibroblasts, vascular smooth muscles cells and pericytes.
PDGFR kinase inhibition is expected to be a useful target for the treatment of various cardiovascular, pulmonary, tissue remodelling and hypertrophic disorders, many cancers and other indications in which PDGF driven functional responses contribute to pathology, including PAH. PDGFR, PDGFR ligands and activated, phosphorylated PDGFR is found in the proliferating smooth muscle cells that comprise the lesions in the pulmonary vasculature of PAH patients and animal models of PAH. Furthermore, the tyrosine kinase inhibitor Gleevec® has been shown to be efficacious in the treatment of PAH clinically and in pre-clinical PAH models. Other targets inhibited by the agents of the invention may contribute to the efficacy of the agents in PAH, asthma and other indications. For example, c-kit inhibition contributes to the depletion of mast cells and is beneficial in the treatment of preclinical models of asthma.